Overuse of medications in low- and middle-income countries: a scoping review

Abstract Objective To identify and summarize the evidence about the extent of overuse of medications in low- and middle-income countries, its drivers, consequences and potential solutions. Methods We conducted a scoping review by searching the databases PubMed®, Embase®, APA PsycINFO® and Global Index Medicus using a combination of MeSH terms and free text words around overuse of medications and overtreatment. We included studies in any language published before 25 October 2021 that reported on the extent of overuse, its drivers, consequences and solutions. Findings We screened 3489 unique records and included 367 studies reporting on over 5.1 million prescriptions across 80 low- and middle-income countries – with studies from 58.6% (17/29) of all low-, 62.0% (31/50) of all lower-middle- and 60.0% (33/55) of all upper-middle-income countries. Of the included studies, 307 (83.7%) reported on the extent of overuse of medications, with estimates ranging from 7.3% to 98.2% (interquartile range: 30.2–64.5). Commonly overused classes included antimicrobials, psychotropic drugs, proton pump inhibitors and antihypertensive drugs. Drivers included limited knowledge of harms of overuse, polypharmacy, poor regulation and financial influences. Consequences were patient harm and cost. Only 11.4% (42/367) of studies evaluated solutions, which included regulatory reforms, educational, deprescribing and audit–feedback initiatives. Conclusion Growing evidence suggests overuse of medications is widespread within low- and middle-income countries, across multiple drug classes, with few data of solutions from randomized trials. Opportunities exist to build collaborations to rigorously develop and evaluate potential solutions to reduce overuse of medications.


Introduction
Overuse in health care is broadly defined as tests or treatments that are inappropriate, unnecessary or of low value and are likely to cause people more harm than benefit. Hence, healthcare overuse is a recognized threat to both human health and health system sustainability. 1,2 Estimates of global overuse suggest that 20-40% of health-care resources may be wasted and that these resources might be better invested tackling unmet need, including underuse. [3][4][5] While much of the evidence for overuse arises from high-income countries, where there is greater access to care, the consequences due to overuse may be even more serious in low-resource settings. 1 For example, medication overuse, a key component of health-care overuse, can threaten both the viability of public budgets, including the universal health coverage, and population health in low-and middle-income countries. 1 Global initiatives such as Choosing Wisely 6 and Preventing Overdiagnosis 7 are increasingly interested in addressing the problem of overuse in low-and middle-income settings. To identify gaps in the evidence-base and develop an agenda for future research and actions, we conducted a scoping review to characterize the evidence about the extent of overuse of medications in these countries, its drivers, consequences and potential solutions to reduce it in low-and middle-income countries. The work has also contributed to building a new global network to take the new agenda forward.

Methods
We conducted this scoping review following the Joanna Briggs Institute guidance, 8 using an accelerated approach, 9 and reported it following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. 10 The protocol was prospectively developed and registered at Open Science Framework. 11

Search strategy
We searched four electronic databases: PubMed®, Embase®, APA PsycINFO® and Global Index Medicus, from inception until 25 October 2021, using a low-and middle-country search filter from Cochrane 12 and without language restrictions. We used a combination of MeSH terms and free text words for the following general concepts: overuse of medications/overtreatment (Box 1; available at: https:// www .who .int/ publications/ journals/ bulletin/ ). We searched reference lists of all included studies, and contacted experts in the field to identify relevant and important grey literature.

Eligibility criteria
We included studies from one or more low-and middle-income countries 13 with a major focus on any of the four medication overuse themes: (i) extent of overuse; (ii) drivers and factors related to overuse; (iii) consequences of overuse; and (iv) solutions addressing the overuses. We included studies reporting data on low-and middleincome countries and high-income countries if data pertaining to low-and middle-income countries could be analysed separately, or the majority (≥ 75%) of reported data were from low-and middle-income countries. For this review, we used a broad commonly used definition of overuse of medications as the provision of medications which are unlikely to benefit the patient given the harms, cost, available alternatives or preferences of the patient -including unnecessary, inappropriate and potentially inappropriate medications. 1,2 We also accepted operational definitions and assessments of primary study authors to estimate the extent of overuse of medications -including using Beers criteria® for Potentially Inappropriate Medication Use in Older Adults, or the screening tool of older persons' prescriptions (STOPP), or appropriateness as judged by local guidelines.
We used the World Bank categorization from 2021 13 to define low-and middle-income countries (available in data repository). 14 We included quantitative interventional and observational studies as well as qualitative studies, both primary and secondary studies, such as systematic reviews of eligible primary studies, and peer-reviewed articles or grey literature (e.g. eligible reports from governmental and nongovernmental organizations and conference abstracts). We included studies regardless of clinical setting (inpatient or outpatient, or the level of care), type of medications assessed (e.g. whether prescribed or nonprescription medications) and population type. We excluded case reports and case series, non-research opinion or analysis, literature reviews, conference abstracts with limited information to judge eligibility or to use for evidence synthesis, and studies where overuse of medications was not a major or primary focus or finding of the study.

Study selection
A total of nine pairs of reviewers independently screened titles and abstracts, and subsequently full text, using an open-access web-based tool. 9 Any disagreements were resolved, at all stages, by discussion or reference to a third author.

Data extraction
We used a prospectively developed and piloted data extraction form. A single reviewer extracted data on (i) study characteristics including sample size and study design; (ii) overuse of medications including conditions and medication studied; (iii) main study themes (extent, drivers, consequences and solutions); and (iv) relevant key findings. For secondary studies (e.g. systematic reviews), we extracted data from summarized information of included studies and not directly from primary studies.

Data synthesis
We grouped studies by a priori defined groups: (i) the major focus or the four main themes; (ii) condition (i.e. per Global Burden of Disease classifica-tion); (iii) countries or country income level; and (iv) medication classes (i.e. by the major categories in the United States Pharmacopeial Medicare Model Guidelines v6.0).

Extent of overuse
Of the included studies, 307 (83.7%; Table 2) reported on the extent of overuse of medications. Overall, the estimates of overuse of medications ranged from 7.3% in a study of 1264 older adults with diabetes in Türkiye (i.e. overtreated with blood pressure lowering and antidiabetic medications) 320 to 98.2% in a study of 599 critically ill older patients (i.e. ≥ 1 potentially inappropriate medications). 141 The IQR of the estimates reported in 307 studies was 30.2-64.5% (Box 2; Fig. 3).
The three most common methods for assessing overuse of medications were: comparing existing prescribing practices with what would be considered appropriate under local professional norms or guidelines (114 studies; 37.1%); using Beers criteria® to identify potentially inappropriate medications (80 studies; 26.1%); and using STOPP (32 studies; 10.4%; Table 2).

Systematic reviews
Overuse of medications Loai Albarqouni et al.

Psychotropic drugs
The estimates of the overuse of antianxiety and antidepressant medications in the 89 studies range from 10.0 % in a survey of 1048 Chilean adults 65 years or older according to Beers criteria® 269 to 91.0 % in a cross-sectional analysis of 456 older adults in a tertiary hospital in India using both Beers® and STOPP criteria. 311 The IQR of the estimates reported in the 89 studies was 30.1-61.7%. There was no study for a low-income country. For 10 lower-middle-and 77 upper-middle-income countries, the estimate ranges were 28.6-87.3% and 31.2-61.4%, respectively (Table 2).

Analgesics, proton pump inhibitors and antihypertensive drugs
A cross-sectional analysis of medical records of 13 274 elderly patients in four community hospitals in Thailand found that 79.0% (10486) of patients were prescribed one or more potentially inappropriate medications, using the Lists of Risk Drugs for Thai Elderly criteria, with antihypertensive drugs, proton pump inhibitors and analgesics being the most frequently prescribed potentially inappropriate medications. 274 Another crosssectional analysis of medical records of 6337 older adults in China found 79.4% (5033) prescribed one or more poten-

Box 2. Examples of key findings in the scoping review on overuse of medications in low-and middle-income countries Estimation of overuse (307 studies; Table 2)
For low-income countries (21 studies), the IQR of overuse estimates was 48.2-82.5%. A cross-sectional study evaluating the appropriateness of antibiotic use for acute diarrhoeal disease among 303 inpatients in a large Ethiopian hospital serving 1.2 million people showed that 86.8% (263) of patients had received at least one antibiotic drug (92.6%; 174/188 of children younger than five years). 343 The rate of overuse of antibiotics was 72.3%, 343 which is a high level of overuse of antibiotics according to the recommendations of WHO for treating diarrhoeal disease. For lower-middle-income countries (63 studies), the IQR of overuse estimates was 26.8-66.2%. A retrospective analysis evaluating the use of potentially inappropriate medicines in 676 elderly patients in an Indian teaching hospital showed that 590 (87.3%) patients received at least one inappropriate medicine according to Beers criteria®, with metoclopramide being the most commonly used inappropriate medication (54.3%; 367 patients). 179 For upper-middle-income countries (205 studies), the IQR of overuse estimates was 29.0-62.5. A cross-sectional study evaluating the prevalence of potentially inappropriate medications among geriatric inpatients in a 3000-bed teaching hospital in China showed that the proportion of potentially inappropriate medications was 64.8% (4163/6424) according to Beers 2019 criteria® and 64.3% (4131/6424) according to Beers 2015 criteria®. Proton pump inhibitors were the most commonly prescribed inappropriate medications. 162

Drivers of overuse (139 studies; Table 3)
A qualitative study explored the drivers of antibiotics overuse in Médecins Sans Frontières projects located in four low-income African countries. The study included 384 people who participated in semi-structured in-depth interviews, focus group discussions, and field observations. System-level drivers included failing health-care systems, such as underdeveloped and understaffed primary and secondary health-care systems. Individuallevel drivers included strong patient demands for antibiotics that influenced prescription decisions, and high proportions of self-medication. 383 Researchers of a qualitative study to identify drivers of potentially inappropriate medication use interviewed 417 geriatric patients in 22 public primary care facilities in Brazil, an upper-middle-income country. Important patient-related drivers included short consultation times (< 10 minutes) and polypharmacy. Clinician-related drivers included the number of patients attended and number of prescriptions per clinician. 43

Consequences of overuse (31 studies; Table 3)
A cross-sectional study examined the costs and appropriateness of prophylactic preoperative antibiotic use among 1000 consecutive patients in six teaching hospitals in the Islamic Republic of Iran, an upper-middle-income country. Antibiotics were prescribed for 85 out of 87 (97.7%) procedures in which an antibiotic was not indicated. The average cost of antibiotic prescription per surgical procedure was US$ 100 and the estimated total cost of inappropriate prescription of cefazoline alone (the most frequently prescribed antibiotic) was US$ 4623; the GDP per capita is US$ 4802. 160 A cross-sectional analysis was conducted of the economic impact of unnecessary proton pump inhibitors in Lebanon, an upper-middle-income country. The proportion of overuse was 71.4% (714/1000 individuals), with an estimated annual waste of US$ 25 million. 170 Solutions for the problem of overuse (42 studies; Table 3) A before-and-after study evaluated the effect of an intervention (training and pulse oximeters) on the appropriate use of oxygen among 1765 patients in a teaching hospital in Rwanda, a low-income country. Oxygen use in the emergency department decreased from a median of 32.0 (IQR: 28.0-35.0) tanks per day to 16.0 (IQR: 12.5-21.0) tanks per day at week 12. The proportion of appropriate use of oxygen therapy increased from 18.7% (34/182) at baseline to 42.0% (42/100) at 12 weeks. 329 A multicentre RCT of the effect of point-of-care CRP testing on the inappropriate use of antibiotics for non-severe acute respiratory infections among 2037 patients in 10 Vietnamese primary health-care centres showed that the number of patients who used antibiotics within 14 days was 581 (64.4%) of 902 patients in the CRP group versus 738 (77.9%) of 947 patients in the control group (OR: 0.49; 95% CI: 0.40-0.61). 115 CI: confidence interval; CRP: C-reactive protein; GDP: gross domestic product; IQR: interquartile range; OR: odds ratio; RCT: randomized controlled trial; US$: United States dollars; WHO: World Health Organization. Note: Results reported in the box are based on key studies that we have selected to represent different countries (i.e. income group or WHO region) and main theme or focus (e.g. solution or estimate). However, these studies were conducted in local settings and might not be representative to the wider low-and middleincome countries context. Therefore, generalizability of these findings to the low-and middle-income countries context is limited and should be done with extreme caution.

Systematic reviews
Overuse of medications Loai Albarqouni et al. tially inappropriate medications according to either Beers criteria® or STOPP, with antihypertensive, anti-anxiety and non-steroidal anti-inflammatory drugs among the most common potentially inappropriate medications. 201

Drivers
Drivers and factors related to the overuse of medications in low-and middle-income countries were reported in 139 (37.9%) studies, with 74 studies reporting on individual-level (i.e. clinician or patient, e.g. knowledge and skills or preferences) and 40 on system-level drivers or factors (i.e. institutional or organization, e.g. resource allocation, staffing and national guidelines; Table 3). Only 10 of these studies were from low-income countr ies, 20,77,111,127,129,144,166,183,262,337 and we did not observe clear associations between country income levels and drivers (Box 2), nor could we observe any geographical variations in the drivers.

Individual-level drivers
Of the studies reporting on individuallevel drivers, 24 studies cited limited knowledge among clinicians or patients on the harms of overuse, 12 studies pointed to perceived or actual patients' demands, while polypharmacy and/or multimorbidity was found as a factor in 38 studies, largely studies of potentially inappropriate medications among elderly people (Table 3). For example, a study of 6400 hospitalized older patients in China found that 64.8% (4147) of prescriptions were inappropriate based on Beers criteria®, with proton pump inhibitors the most common potentially inappropriate medication, and polypharmacy was the most important factor associated with potentially inappropriate medications. 162 In a qualitative study with clinicians and older adults in Burkina Faso, a low-income country, drivers of overuse included poor patient-clinician communication, limited clinician knowledge, and incentives from pharmaceutical companies. 163

System-level drivers
Of the studies reporting on system-level drivers and factors, 11 studies cited regulatory issues such as poorly enforced regulations or policies; 16 studies cited constrained resources, including limited access to diagnostic facilities, and problematic access in rural or regional places; and 13 studies cited financial factors  [173][174][175]183,190,193,194,196,198,199,204,206,208

Consequences
Consequences of overuse of medications were reported in 31 studies (8.4%), including just one from a low-income country (Table 3). 21 The two most commonly identified consequences of overuse were harms -such as adverse drug reactions, impacts on quality of life or mortality -and costs. For example, a study among 125 heart-failure patients in Lebanon found a moderate correlation between potentially inappropriate medications and reduced quality of life, 374 while another small study of 127 older adults in Brazil found no impact of potentially inappropriate medications on mortality, during a 10-year followup. 111 In relation to costs, a study in the Islamic Republic of Iran estimated that almost 1 million United States dollars (US$) was wasted within a year in one teaching hospital on unnecessary antibiotics, measured as use not adherent to local guidelines. 292 In 2020, a survey in Lebanon found widespread overuse of proton pump inhibitors and estimated that the nation may be wasting US$ 25 million annually as a result. 170 No studies in low-income countries assessed costs of overuse.

Potential solutions
Evaluations of potential solutions were reported in 42 studies (11.4%), with 23 studies reporting on interventional rather than observational studies (Table 3).
Only four studies of solutions were based in low-income countries 231,249,329,335 (data repository). 14 Twenty-two studies of solutions focused on antibiotics (Table 3). For example, a review identified multiple interventions that successfully reduced inappropriate antibiotics in low-and middle-income countries, including national action plans, educational campaigns, wider use of audit-feedback initiatives and regulatory or legal changes to reduce self-purchasing of antibiotics. 145 Similarly, a large study of long-term antibiotic use in 55 low-and middle-income countries, using World Health Organization databases, found that having national policies and/or strategies on rational antibiotic use was associated with an estimated 20% reduction in antibiotic use for upper respiratory tract infections and an estimated 30% reduction in antibiotic use for acute diarrhoeal illness. 167 For non-antibiotic overuse, 20 studies evaluated potential solutions, including educational interventions, deprescribing initiatives, new technologies and interventions involving pharmacists (Table 3). In Uganda, a lowincome country, two cluster randomized controlled trials of 127 villages and 381 community health workers found dramatic reductions in the overuse of antimalarial drugs following the introduction of rapid diagnostic tests (48.5% absolute reduction: from 79.3%; 520/656; to 30.8%; 215/699). 247,388 In Argentina, a multifaceted intervention including educational workshops, deprescribing algorithms and automated email alerts was found to successfully reduce inappropriate medications among 900 older adults (overall absolute reduction of 8.5% across eight classes of potentially inappropriate medications -relative reduction of 73% for nonsteroidal anti-inflammatory drugs and 31% for benzodiazepines). 303 Also in Argentina, an email-linked behavioural intervention underpinned by socialnorm feedback reduced inappropriate prescriptions and cost for cognitively impaired older adults. Physicians in the intervention group made fewer inappropriate prescriptions than physicians in the control group, mean 93.25 prescriptions (95% CI: 89.27-97.24) versus 98.99 (95% CI: 95.00-102.98). 341 In Thailand, a large study of 11 915 patients across four community hospitals found that computerized decision support systems that detect potentially inappropriate medications were associated with 13.3 percentage points decrease (from 87.7% to 74.4%) in potentially inappropriate medications. 275 A 2021 Chinese study found that an intervention by clinical pharmacists halved the rate of inappropriate prescriptions of proton pump inhibitors (from 48.9 to 22.7 prescriptions per 100 patient-days), with no harmful impacts. 378 Encouragingly, a 2018 sur-vey in Ethiopia, a low-income country, assessing attitudes to deprescribing, found that 81.6% (258/316) of people asked were willing to stop one or more medications if possible and if agreed by their doctors. 335

Discussion
We found widespread evidence of high proportions of overuse of medications in low-and middle-income countries. Classes of commonly overused medications included antibiotics, benzodiazepines, non-steroidal anti-inflammatory drugs, proton pump inhibitors and antihypertensive medicines. Drivers of overuse included a lack of knowledge of overuse among patients or clinicians, insufficient resources to access optimum care, polypharmacy, financial factors including the profit motive, and weak or poorly enforced regulations. Consequences were harms from adverse drug reactions and high costs of inappropriate use of scarce resources. While only a small number of studies evaluated potential solutions, we identified feasible and effective interventions, even for the lowest income settings, to tackle the problem of overuse.
Almost 90% of the included studies were published in the past 10 years, emphasizing the growing interest in understanding and addressing overuse of medications in low-and middle-income countries. We observed wide dispersions of the proportion of overuse of medications; this finding might be attributed to the differences in the population, settings, medications and methods used among included studies. Only a few studies evaluated the consequences, such as financial wasting. Wasting of resources is catastrophic for health-care systems in low-and middle-income countries that are already fragmented and fragile. 389 Future research should not only estimate the extent of overuse of prescribed medications, but also estimate the extent and drivers of the overuse from nonprescription medications. Furthermore, studies should evaluate the potential physical, psychological and social consequences, both at individual and health-care system levels. Further research should also include improving the methods to evaluate the harms and consequences associated with overuse of medications.
The finding that only a tenth of studies evaluated potential solutions Overuse of medications Loai Albarqouni et al.
points to a gap in the literature and the need to intensify research evaluating innovative solutions to reduce overuse, while at the same time improving the rigor of the science assessing the extent and nature of the problem. Our review finds evidence from low-and middle-income countries of significant reductions in inappropriate medications, using for example multifaceted interventions or deprescribing initiatives, which suggests such interventions are practical as well as desirable. However, future studies replicating successful interventions from high-income countries need to include more robust evaluations of individual-level (e.g. educational interventions, audit and feedback, and clinical decision support system) and system-level solutions (e.g. changes in payment and incentives and changes in regulations and policies). 390 We also found strong evidence of very high levels of overprescription of antibiotics across many low-and middle-income countries. Such overprescription is associated with antibiotic resistance, 391 however, there are hopeful signs that those overprescription rates can be reduced with national policies and local initiatives. 145, 167 Research evaluating potential solutions for unnecessary prescription needs to focus on nonprescription antibiotic dispensing in drug shops and antibiotic prescriptions by private health-care providers. This research might include multicomponent interventions combining educational programmes to improve public awareness; engagement of pharmacists in patient education and consumer guideline development; audit and feedback; and more incisive regulations and policies to reduce inappropriate antibiotic use in low-and middle-income countries. 392 Our finding that only 7% of studies were from low-income countries suggests that either the problem of overuse may not be so pressing in places where underuse is a clear priority for stakeholders, or that the problem of overuse is understudied.
Our review has limitations. To achieve the breadth required of a scoping review, we have necessarily included studies using a range of definitions and methods, from assessing adherence to guidelines for appropriate use, to the potentially inappropriate medications assessments using the Beers criteria®, STOPP and other criteria. While we broadly accepted the definitions used by authors of the studies, if our review team could find no evidence in the study of an explicit method to measure overuse, the study was excluded. Generally, definitions of inappropriate use equate to use when a medication is not clinically indicated, or the overuse of a medication which may bring more harm than benefit, but in some studies, use of the term inappropriate also included finer details relating to dosage, frequency or duration of use. A further limitation arises from our subjective categorization of systemversus individual-level drivers, where there may be clear overlap among these drivers. Another minor limitation arises from applying the World Bank income level list from 2021 to studies conducted over many previous years, however, the income level has not changed for most low-and middle-income countries. 13 The findings of this review suggest the time has arrived to build a global community of researchers, clinicians, policy-makers and citizens who will share, build and improve the science of overuse in low-and middle-income countries. The global community should have a focus on scaling up effective solutions to reduce harm and save wasted resources. Initiatives to tackle overuse of medications in low-and middle-income countries are currently limited and of a particular focus -such as the Global Antimicrobial Resistance Partnership. 393

Systematic reviews
Overuse of medications Loai Albarqouni et al.